Evaluating the cost-effectiveness of HCC treatments is crucial for guiding clinical decisions. As new drugs and regimens are introduced rapidly, assessments of the economic value of systemic therapies need frequent updates^[5,13,15]. The goals of this study were to gather evidence on: (1) the comparative economic effectiveness, utility, and benefits of HCC treatment options; and (2) factors that influence treatment costs, including perspectives from clinicians, hospital managers, policymakers, patients, and stakeholders. The review also examined international differences in financial aspects among providers, payers, and regions. In this scope, we specifically focused on first- and second-line systemic therapies.

The primary research question of the entire project was: What are the most cost-effective treatments for patients with HCC?

Within this framework, the research question of the current study was: What are the most cost-effective first- and second-line systemic therapies for patients with HCC?

We used the P (patients/disease), I (interventions), C (comparators), and O (outcomes) framework, where patients were those affected by HCC; interventions included all active strategies for treating HCC, both curative and palliative; comparisons involved best supportive care (BSC) or comparisons across treatments; and outcomes measured economic treatment metrics. Therapeutic interventions were based on the 2025 EASL guidelines for HCC treatment. These were categorized into (1) ablation; (2) intra-arterial therapies; and (3) systemic therapies^[19]. Ablation includes conventional or drug-enhanced radiofrequency ablation (RFA) or microwave ablation (MW), selective internal radiotherapy (SIRT), stereotactic body radiation therapy (SBRT), liver resection (LR), and LT. Intra-arterial therapies included hepatic artery infusion chemotherapy (HAIC) and trans-arterial chemoembolization (TACE). We also expanded the research to include treatments not yet fully explored by the EASL guidelines, such as carbon ion therapy (CIT). Based on the available studies, these treatments were considered either alone or in combination.

Comparative economic evaluations were defined per international standards as cost-minimization analysis (CMA), cost-benefit analysis (CBA), cost-effectiveness analysis (CEA), cost-utility analysis (CUA), and cost-of-illness analysis (COIA)^[24,25]. COIA papers were excluded because they lacked a comparator population^[25,26]. Considerable overlap exists among these methods, particularly between CEA and CUA, and classifications vary across authors^[27-29].

PubMed (PubMed.gov), Google Scholar (https://scholar.google.com/), Cochrane (Wiley Online), Scopus, Web of Science (WoS), and Embase (Embase.com) were searched on July 1, 2025. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guidelines were used to define the study’s eligibility criteria, conduct quality assessment, and analyze the results^[30,31]. A PRISMA checklist for the abstract and paper is provided as Supplementary Materials.

The search terms used to retrieve the studies are illustrated in the Supplementary Materials. Only full-length articles in English or in English translations were included. Systematic reviews, commentaries, empirical articles, gray literature, trade publications, and digital media communications were excluded and used only to retrieve additional references not included in the original search strategy. Owing to various factors, such as the rising healthcare costs of HCC treatment^[4,8], advancements in recent medical technologies for HCC, shifts in liver disease epidemiology with the emergence of metabolic dysfunction-associated liver disease (MASLD), and the increasing number of publications on HCC, the literature review was limited to studies published between 2015 and June 30, 2025. However, if the thematic coverage was insufficient, a second search was conducted without date restrictions, and key or seminal papers on the topic, along with other relevant manuscripts, were considered, regardless of their publication date.

Only articles comparing first- or second-line systemic treatments to active comparators, placebo, or BSC were included in the final analysis. Studies involving neoadjuvant or adjuvant therapies administered before or after radiology-assisted interventions or surgery, and systemic therapies compared with intrahepatic arterial infusion, were excluded.

The references were initially evaluated independently by two investigators (Longo D and De Simone P) based on the face value of their abstracts, with any disagreements resolved by a third reviewer (Peritore D). The reference lists of the articles were also checked for additional literature (snowballing). An artificial intelligence (AI)-based Rayyan platform was used to sort articles, assess abstracts and texts, and eliminate duplicates (https://www.rayyan.ai/). A shared Google Drive repository was used to collect and review articles from all team members.

Extracted variables included year, authors, title, study type, country, population, interventions and comparators, and effectiveness measures [quality-adjusted life-years (QALYs) or life-years saved (LYS)]. Costing methods, time horizons, discount rates, currencies, sensitivity analyses, reported costs, and economic metrics were also recorded. HCC stage was classified according to the BCLC system, and interventions were categorized as curative or non-curative. International currencies were converted to US dollars using a currency converter^[32]. No inflation adjustments were made to reported monetary values. Outcomes were assessed using three primary metrics: (1) QALYs and LYS as measures of clinical benefit; (2) incremental cost-effectiveness ratio (ICER) per QALY/LYS [or incremental cost-utility ratio (ICUR)] to show additional cost per unit benefit; and (3) ICER/willingness-to-pay (WTP) ratio to indicate cost-effectiveness, using WTP values reported in the studies or, when absent, the World Health Organization (WHO) guidance calculating WTP as three times the per capita gross domestic product (GDP)^[33]. Data interpretation followed Sukhera^[21].

The comparator was SORA in 10 (90.9%) studies^{[34-39,41-44]}, and NIV in one (0.9%)^[40]. All these studies based their economic analyses on the IMBrave-105 trial^[90]. The analysis comparing ATE + BEVA vs. NIV also used data from the CheckMate-459 trial^[91]. The studies were published between 2021 and 2025 and examined cost-effectiveness in China in four (36.4%), Taiwan in two (0.18%), and Thailand (0.9%), Singapore (0.9%), France (0.9%), the USA (0.9%), and both the USA and China (0.9%). The adjusted mean (SD) of ATE + BEVA QALYs was 0.70 ± 0.36, and the adjusted mean ± SD of LYS was 1.21 ± 0.11. The adjusted mean ± SD ICER/WTP ratio is 2.71 ± 3.07. Finally, ATE + BEVA was cost-effective (i.e., ICER/WTP < 1) compared to the comparator in four studies (three versus SORA and one versus NIV) [Table 1]^{[36,38,39,40]}.

Four studies published between 2021 and 2023 examined the cost-effectiveness of SIN (a PD-1 receptor antagonist approved for HCC in China) in combination with BEVA or a BEVA biosimilar (IBI3015)^[44-48]. All of these studies were conducted by Chinese authors, with SORA as the comparator in three studies and LEN in one study^[44-48]. The studies derived data for analysis from previous trials, that is ORIENT-32^[92], and REFLECT^[93]. The adjusted mean ± SD of the SIN + BEVA biosimilar QALYs was 0.64 ± 0.42, and the reported LYS (measured in only one study) was 1.84. The adjusted mean ± SD ICER/WTP ratio is 1.06 ± 0.55. Finally, the SIN + BEVA biosimilar was cost-effective in three studies (two versus SORA, and one versus LEN) [Table 1].

The STRIDE regimen was studied in three research projects between 2023 and 2025, involving scholars from the US (2 cases) and China (one)^[49-51]. All studies used data from the HIMALAYA trial^[94]. One study also compared DUR monotherapy with STRIDE^[50]. The mean ± SD adjusted QALY for STRIDE was 0.35 ± 0.19, and the reported LYS (measured in only one study) was 0.27. The mean ± SD adjusted ICER/WTP ratio was 0.42 ± 0.26, and STRIDE proved cost-effective across all included studies, regardless of the TKI/VEGFi comparator^[49-51].

A regimen combining CAM (a PD-1 inhibitor approved in China) with RIV (a VEGF-2 inhibitor approved in China and pending approval in other countries) was studied in two research projects by Chinese scholars, one examining China’s healthcare system and the other exploring both the US and Chinese healthcare systems [Table 1]^[52,53]. Data were derived from the CARES-310 trial in both cases^[95]. The adjusted mean ± SD QALY for CAM + RIV was 0.71 ± 0.08, and the adjusted mean ± SD ICER/WTP ratio was 0.71 ± 0.43. CAM + RIV was found to be cost-effective in both published studies^[52,53].

A single-agent regimen with TIS, a PD-1 inhibitor, was compared with SORA in three studies conducted by Chinese researchers, examining cost-effectiveness in China (two publications) and across China, the USA, and Europe (one publication) [Table 1]^[54-56]. In all studies, data were derived from the RATIONALE-301 trial^[96], and the comparator was SORA. The adjusted mean ± SD QALY for TIS was 0.46 ± 0.18, and the adjusted mean ± SD ICER/WTP ratio was 0.58 ± 0.27. The regimen was cost-effective in all studies and across all international scenarios [Table 1]^[54-56].

A single-agent regimen with NIV, a PD-1 inhibitor, was compared with SORA in two studies conducted between 2022 and 2023, both of which evaluated its cost-effectiveness in China^[57,58]. Population data were obtained from the CheckMate-459 trial for each case^[91]. Despite its improved clinical efficacy over SORA (i.e., adjusted mean ± SD QALY of 0.29 ± 0.03), NIV was not considered cost-effective in any of the studies (adjusted mean ± SD ICER/WTP ratio 3.83 ± 3.33) [Table 1]^[57,58].

In 2020, a US study examined eight different sequences of first- and second-line drugs using VEGFi and/or TKI agents [SORA, regorafenib (REGO), cabozantinib (CABO)], LEN, and ICIs [pembrolizumab (PEM), a PD-1 inhibitor, and NIV]^[59]. The sequences included SORA - REGO, SORA - CABO; SORA - NIV, SORA - PEM, LEN-REGO, CABO; LEN - LEN-NIV, and LEN-PEM [Table 2]. Data were obtained from randomized controlled trials (RCTs) of the respective drugs. Although utility outcomes (such as QALYs) were not available, the study indicated that a strategy of TKI/VEGFi followed by ICI upon disease progression is more cost-effective than using TKI/VEGF as both first- and second-line therapies^[59]. The two most cost-effective regimens were SORA - PEM (ICER = US$227,741.03) and LEN - PEM (US$230,371.17). However, both regimens were above the WTP national threshold of 150,000 USD^[59].

Nine studies published between 2021 and 2024 compared multiple first-line regimens simultaneously^[60-68]. Detailed information about the authors of the studies, publication years, national health systems examined, QALY/LYS, ICER, WTP, and ICER/WTP are shown in Table 2. Seven of these studies examined the cost-effectiveness of ICI- and TKI/VEGFi-based schedules together^{[60,62-65,67,68]}; one focused only on TKI/VEGFi^[66], and one included only ICI therapies^[61]. Eight studies included SORA in their comparisons^[60,62-68]. In one study, the most cost-effective regimens were donafenib (DONA)^[67], a deuterium derivative of SORA approved for unresectable HCC in China in 2021^[97,98]; DUR monotherapy^[60]; SIN + BEVA biosimilar^[61]; ATE + BEVA^[62]; CAM + RIV^[61]; LEN^[62], and sunitinib (SUN) [Table 2]^[65].

All 54 studies were initially assessed for eligibility and risk of bias using the JBI assessment grid, which includes 11 items^[88]. The detailed reports of these studies are shown in Table 5. Due to the large number of included studies, responses to the 11 items of the JBI are summarized collectively. Three qualitative items were poorly addressed across the included studies: (1) the comprehensive description of available therapeutic options; (2) the credibility of economic metrics; and (3) the transferability of results. No study evaluated all therapeutic regimens currently available in a specific health market. Cost-effectiveness metrics were not credibly reported in five studies: in four cases, WTPs exceeded those recommended by the WHO^{[40,58,82,83]}, and in one case, WTP was lower than that based on national GDP^[62]. Four studies did not report any WTP^{[68,70,71,84]}. The transferability of results should be interpreted cautiously for studies exploring only the Chinese market (26 studies) or the Chinese market in combination with the USA (4 studies) or the USA and Europe (1 study), given the different dynamics of drug reimbursement policies [Tables 5-8]. Finally, 14 studies focused on or included drugs and regimens currently approved only in the Chinese market [Tables 5-8]. The Supplementary Table 1 provides a complete list of systemic treatments approved in China, the USA, and Europe at the time of publication.

Further assessments were performed using the ECOBIAS checklist^[89], as shown in Table 6. Metrics of utility, such as QALYs, were reported in nearly all included studies (52 = 96.3%), whereas effectiveness measures, such as LYS, were reported in 15 (27.8%) studies [Table 6]. ICERs were reported in 49 (90.7%) studies, with 2 (3.7%) using ICURs^[43,70]. Three studies (5.5%) employed alternative outcome measures such as cost savings or ICER per month of PFS^[66,68,74]. WTPs were documented in all studies except 4 (92.6%)^{[68,70,71,84]}. Notably, no CBA has been reported in the international literature on systemic therapies for advanced HCC during the study period.

Almost all studies collected data from published trials on systemic therapies or from network meta-analyses of published trials (51/54, 94.4%)^[90-103]. This limited the ability to accurately count patients included in the review, owing to the risk of double-counting participants from the trials used for cost-comparative assessments. Real-world data were only available from a study in France on ATE + BEVA^[39], a survey of SORA from the USA using SEER program (https://seer.cancer.gov/registries/)^[86], and a study from China comparing SORA to placebo/BSC^[87]. Most studies (28/54, 51.8%) used a partitioned survival model, which included PFS, progressive disease (PD), and death, to estimate cost-effectiveness [Tables 1-4]. Twenty-three studies (42.6%) employed a Markov state-transition model, one (1.8%) used a decision analytic approach^[79], one combined propensity score matching with univariate and multivariate survival analysis^[86], and one (1.8%) did not clearly specify the methodology for calculating transitions across health states for patients on systemic therapy [Tables 1-4]^[68]. A lifetime horizon was used to estimate the costs of the therapies in 15 studies (27.8%) [Tables 1-6]. In 21 studies (38.9%), the median [interquartile range (IQR)] timeframe was 10 (9) years [Tables 5 and 6]. However, this was not clearly specified in the remaining 18 studies (33.3%) [Tables 1-4].

A national or regional healthcare system perspective was used in 18 studies (33.3%). A payor’s perspective was employed in nine studies (16.7%), whereas a societal perspective was adopted in three studies (5.5%). It was not clearly specified in 24 studies (44.4%) [Tables 1-6].

Tables 7 and 8 provide details on the types and numbers of treatments explored, as well as their distribution across countries. While the overall number of treatments differs only slightly between China and the USA, more treatments were investigated more than once in China [Table 7]. In Chinese studies, among 18 treatments/regimens, LEN was investigated 12 times; ATE + BEVA, 11 times; SIN + BEVA biosimilar, 10 times; DONA, 5 times; and TIS, 4 times. Further treatments were investigated 3 times [Table 7]. Of the 17 treatments investigated in US papers, the most frequently explored were ATE + BEVA (3 times)^[35,43,62]; and STRIDE (2 times)^[49,50]. In Europe, only 5 treatments were explored, with ATE + BEVA being the most frequently investigated regimen (2 times)^[39,68].

Overall, the main finding of our review was that 14 (40.0%) of the 35 treatments compared in the literature demonstrated some degree of cost-effectiveness, with only a third of the included studies (18/54) reporting it [Tables 1-4, 7 and 8]. These treatments included 9 first-line ICI-containing regimens, 3 first-line TKI/VEGFi schedules, and 2 sequencing treatments [Table 8]. Among first-line treatments, ICI-containing regimens were more often cost-effective than other active drug regimens^[34-87], and LEN outperformed SORA more frequently than the other targeted oral agents (i.e., DONA, SUN). These results align with the superior clinical effectiveness of these regimens in phase II and III trials [Tables 1-4, 7 and 8].

Finally, despite its widespread use until the introduction of LEN and/or ICI-containing regimens, SORA was not proven to be cost-effective compared to placebo or BSC^[84-87]. However, no study has evaluated the ICER of generic SORA formulations introduced into clinical practice over the past few years. The lack of these studies is likely due to SORA’s inferior clinical effectiveness compared to more recent LEN and/or ICIs.

Second-line therapies after the failure of initial oral agents have not shown cost-effectiveness for any of the drugs studied (CABO, REGO, PEM, and RAM) when compared to placebo or BSC^[76-83]. This is because the limited improvements in OS and PFS do not justify the high costs of these medications. Only one US study evaluated the cost-effectiveness of eight treatment sequences involving both first- and second-line agents^[59]. Despite limitations from a multiple-comparator analysis using data from randomized clinical trials of six different agents, the study found that two combinations were cost-effective: SORA-PEM and LEN-PEM^[59]. However, these results should be revisited given the proven superiority of ICIs over SORA as first-line options.

Overall, these findings from comparative economic analyses of first- and second-line agents/regimens do not conflict with clinical data but instead underscore the economic burden of introducing new drugs into the healthcare market. Drug prices were the main cost factor in all the included studies, and strategies to reduce these costs may lower the value of ICERs and enhance the ICER/WTP ratios^{[42,43,70,71,74,75,81,82]}.

An important finding of this research is that most studies were conducted by Chinese authors or focused on the Chinese medical market^[34-87]. Overall, 48.1% (26/54) of the papers examined only the Chinese market, 4 (7.4%) combined China and the USA, and one (1.8%) investigated the Chinese, US, and European markets. This is due to the epidemiological importance of HCC in China, as well as the fact that more first- and second-line agents have been approved for use in China than in other countries or regions [Supplementary Table 1]. To our knowledge, 14 drugs or treatment regimens have been approved for advanced HCC in China as of the publication of this paper, and at least nine targeted agents or combination regimens were recommended by experts in 2024, including SORA, LEN, DONA, ATE + BEVA, SIN + BEVA/BEVA biosimilar, and second-line options such as REGO, CABO, and apatinib.

However, this apparent dominance decreased when comparing the number of treatments studied across different countries or regions, especially for China and the USA [Table 7]. Despite having more publications, the number of regimens examined was nearly the same in Chinese papers (n = 18) and studies from the USA (n = 17) [Tables 1-4 and 7]. Topic redundancy was observed among Chinese researchers, who studied LEN in 12 publications, ATE + BEVA in 11, SIN + BEVA biosimilar in 10, DONA in 5, and TIS in 3 [Table 7]. A clear reason for this redundancy is hard to determine but may be linked to publication pressure on Chinese researchers, the size of China’s healthcare market, the epidemiology of HCC in China^[106], the complex economic factors across different Chinese regions, and the requirements for obtaining marketing approval from Chinese authorities. Lastly, various Chinese pharmaceutical companies have developed and produced a significant portion of systemic drugs for HCC, including CAM, RIV, SIN, various BEVA biosimilars, and DONA, and they obtained marketing approval earlier than in other countries [Supplementary Table 1].

This geographical imbalance in the literature on systemic treatments for HCC calls for caution when applying the review’s conclusions to countries outside China and Asia. Macroeconomic factors (such as national GDPs, WTPs, drug reimbursement policies, patient co-payments, drug pricing, discount rates, manufacturer competition, regulation of generic versus brand-name products, etc.) and microeconomic elements (like access to care and medications, patients’ social status, neighborhood deprivation, availability of family support or caregivers, etc.) are not always clearly included in comparative economic analyses and continue to affect the benefits and usefulness of systemic drug treatments for advanced HCC.

Several key issues were identified across the studies included in this review, as shown in Tables 5 and 6. Only a small number of studies addressed multiple comparators^[59-67], and only a few were based on real-world data^[29,86,87]. This is because nearly all studies relied on phase II/III trials^[90-103], with limited use of post-registration clinical evidence. With the notable exception of SORA, which was approved for use in the USA, Europe, and China between 2007 and 2008, and oxaliplatin-containing regimens approved in China in 2013, all other systemic agents have been approved more recently, from 2017 onward [Supplementary Table 1]^[106,107].

Post-registration, clinically focused economic analyses are crucial for better linking evidence to real-world practice. This is because initial drug prices typically decrease over time due to annual discounts, contracting, and competition from new therapies. Additionally, as treatments evolve, approved indications often expand to include patient groups not covered in registration trials^[90-103]. Patient selection in randomized clinical trials is usually stricter than in real-world settings, and exclusion criteria - such as bleeding, ascites, and liver decompensation - remain relevant for many patients needing treatment, especially considering their shorter lifespan^[90-103]. Finally, issues like temporary drug withdrawal, dose adjustments due to adverse events, and the use of surgery, radiological procedures, or switching drugs are not addressed in the original trials used for marketing authorization. Therefore, it is not surprising that the societal perspective was considered in only a small percentage of the included studies (5.5%), and that issues of concern to patients (e.g., access to care, work disability, loss of income, etc.) were overlooked in the current review.

We acknowledge that, since our review relies on the published literature, it may not encompass all relevant economic analyses on the topic. First, financial information on HCC treatments may be shared not only through scientific publications but also via manufacturers’ reports, drug leaflets, digital media coverage, and administrative sources. Additionally, economic evaluations of systemic drug treatments might have been communicated only to hospital administrators and/or policymakers, rather than being included in peer-reviewed reports or publications. Furthermore, adjustments are often needed in health economic studies to account for inflation, disparities in resource allocation methods, and differences in pricing and reimbursement policies [such as disease-related group (DRG) tariffs, co-pays, and out-of-pocket systems]. These adjustments are not always reflected in scientific reports and often require experience with a specific national or regional market to incorporate them into comparative economic analyses. Finally, elements of current economic instability - such as increased tariffs on exports to the USA and reduced availability of components from manufacturing countries - can undermine the reliability of analyses and forecasts.

The transferability of the results of this review should therefore be interpreted with caution and considered within the context of each national or regional setting where systemic drugs for advanced HCC are used. Aside from the geographical differences and the methodological limitations previously mentioned, the ultimate cost-effectiveness of systemic treatments depends on the ICER/WTP ratio. The WHO guidelines recommend that the national WTP be set at a level aligned with per capita GDP, ranging from 1 to 3 times that amount^[33]. Since GDPs vary across and within countries, ICER/WTP ratios differ between studies and over time. Furthermore, although ICER/WTP measures access to treatment in a specific scenario, it often does not fully reflect true cost-effectiveness. National or regional health authorities and administrators may override this ratio for treatments with proven clinical importance, such as those for malignancies or rare diseases, especially when effective options are limited. Policymakers and stakeholders might also implement policies that reallocate financial resources from less effective treatments to more costly ones, thereby increasing access for underserved populations.

Interestingly, the method commonly used to evaluate the cost-effectiveness of systemic therapies for advanced HCC in this review relies on direct comparisons between treatment regimens or schedules, such as ICI-containing regimens versus VEGFi. In nearly all included studies, SORA was used as the standard control against the experimental treatment arm(s). Although this reflects the design of the registration trials used for comparative economic calculations, real-world data suggest a shift from SORA to LEN, a decrease in the use of oral agents as first-line therapies following the advent of ICIs, and an increase in their use as second-line treatments for patients with limited tumor progression^[108,109].

Finally, the comparative approach used in the reviewed papers faces challenges due to the increasing adoption of combination strategies in clinical practice for the treatment of advanced HCC^[14,108,109]. While systemic therapies were initially viewed as alternatives for patients with advanced tumors who were ineligible for surgery (including resection and LT) or radiology-guided procedures, the current clinical landscape shows a growing use of combination approaches. These include systemic therapies, such as neo-adjuvant or adjuvant treatments, or bridging modalities to enhance surgical or radiological outcomes^[108,109]. One example of these innovative approaches is the recent approval by Chinese authorities of PEM in combination with LEN and TACE, emphasizing the need for appropriate methodologies to evaluate their cost-effectiveness in real-world settings.

Building on the analysis of accessible comparative economic data, the secondary goal of this review was to raise awareness of strategies to enhance the cost-effectiveness of systemic therapies for advanced HCC. These strategies are shown in Table 9 and are based on Bronfenbrenner’s ecological systems theory^[110], which suggests that implementing interventions should involve three levels: the micro-level (the healthcare provider-patient dyad), the meso-level (healthcare organizations), and the macro-level (administrators, policymakers, stakeholders, and society at large). These initiatives should engage all participants involved in caring for patients with advanced HCC, including patients, healthcare providers, healthcare organizations, administrators, policymakers, stakeholders, and scientific societies, and should develop suitable methods to address the complexities of caring for advanced HCC patients.

In conclusion, our systematic review highlights significant variability in comparative economic analyses of systemic therapies for HCC across and within national and international settings. These differences mainly arise from study methodologies, time horizons, drug costs, and the perspectives used (such as societal versus healthcare systems), rather than from the sources of the datasets. However, based on current evidence, ICIs tend to be more cost-effective as first-line agents than any other active comparators studied. Among the oral agents, LEN is more cost-effective than SORA, and both SORA-PEM and LEN-PEM appear to be the most cost-effective sequencing strategies in the single study investigating these drug sequences. Changes in clinical practice, driven by the expansion of systemic therapies beyond their original indications and their combination with radiology-assisted techniques or surgery, necessitate aligning the methodologies of future studies with economic evaluations. A standardized approach to cost-effectiveness research, along with regular updates, is therefore essential given the rapidly evolving clinical landscape and the need to offer patients the highest standard of care.